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Correlated Electrostatic Mutations Provide a Reservoir of Stability in HIV Protease
2012
PLoS Computational Biology
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HIV protease, an aspartyl protease crucial to the life cycle of HIV, is the target of many drug development programs. ...
Using a coarse-grained biophysical energy model together with statistical inference methods, we observe that accessory mutations of charged residues increase protein stability, playing a key role in compensating ...
Acknowledgments We thank Emilio Gallicchio for many discussions and assistance with implementation of the coarse-grained Generalized Born electrostatic model.
Author Contributions ...
doi:10.1371/journal.pcbi.1002675
pmid:22969420
pmcid:PMC3435258
fatcat:yki2eeqgdbb2vknunji5pdlk7u
Molecular Basis for Reduced Cleavage Activity and Drug Resistance in D30N HIV-1 protease
[article]
2021
bioRxiv
pre-print
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AbstractNelfinavir is one of the FDA approved HIV-1 protease inhibitors and is a part of HAART therapy for the treatment of HIV-AIDS. ...
Here, we have determined structures of D30N HIV-1 protease in unliganded form and in complex with the drug nelfinavir. ...
Acknowledgement We thank late Dr Jean -luc Ferrer, FIP beamline, ESRF, for help in data collection and processing. ...
doi:10.1101/2021.02.28.433284
fatcat:qqanmvtaxbf2xbivjzvjyz7dce
Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3
2007
Retrovirology
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We have obtained the 1.7 A crystal structure of FIV protease (PR) in which 12 critical residues around the active site have been substituted with the structurally equivalent residues of HIV PR (12X FIV ...
However, the flap regions of the 12X FIV PR more closely resemble those of HIV PR, having gained several stabilizing intra-flap interactions not present in wild type FIV PR. ...
Mutations that increase stability in the flap allow a degree of cleavage of HIV substrates by FIV, but levels do not approach that obtained by HIV PR [17] . ...
doi:10.1186/1742-4690-4-1
pmid:17212810
pmcid:PMC1781954
fatcat:6zuizgjuxffmfmte3k47p7hyge
Structural basis for drug and substrate specificity exhibited by FIV encoding a chimeric FIV/HIV protease
2011
Acta Crystallographica Section D: Biological Crystallography
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PDB References: 6s-98S FIV protease with darunavir bound, 3ogp; with lopinavir bound, 3ogq. ...
structure of wild-type HIV protease (Tie et al., 2004) . 3kfn is a complex of wild-type HIV protease with TL-3 and allosteric fragment 4D9 (Perryman et al., 2010) . 1b11 is a TL-3bound crystal structure ...
Replacement of residues in FIV PR with homologous residues from HIV PR to create chimeric enzymes provides a system in which inhibitor specificity and pathways of drug-resistance development can be probed ...
doi:10.1107/s0907444911011681
pmid:21636894
pmcid:PMC3107052
fatcat:zziq3bzmjfhi3hvli5zv3w77ze
Molecular Analysis of the HIV-1 Resistance Development: Enzymatic Activities, Crystal Structures, and Thermodynamics of Nelfinavir-resistant HIV Protease Mutants
2007
Journal of Molecular Biology
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The combination of the D30N and L90M mutations significantly increases the enzyme vitality in the presence of nelfinavir, without a dramatic decrease in the catalytic efficiency of the recombinant enzyme ...
Vitality values obtained for recombinant mutant proteases and selected PR inhibitors confirm the crucial role of mutations in positions 30 and 90 for nelfinavir resistance. ...
Acknowledgements This work was supported by grant NR/8571-3 from the Ministry of Health Care of the Czech Republic and by a grant from the Ministry of Education (MSMT) of the Czech Republic within programs ...
doi:10.1016/j.jmb.2007.09.083
pmid:17977555
fatcat:g537eq4v3bchdc6v5r6vqioeoe
Structural mechanism for HIV-1 TAR loop recognition by Tat and the super elongation complex
2018
Proceedings of the National Academy of Sciences of the United States of America
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Promoter-proximal pausing by RNA polymerase II (Pol II) is a key regulatory step in human immunodeficiency virus-1 (HIV-1) transcription and thus in the reversal of HIV latency. ...
Here, the crystal structure of the TAR loop in complex with Tat and the SEC core was determined at a 3.5-Å resolution. The bound TAR loop is stabilized by cross-loop hydrogen bonds. ...
Different approaches to a cure for HIV-1 infection include elimination of all viral reservoirs following reactivation of the latent provirus (referred to as shock and kill), immune control without reservoir ...
doi:10.1073/pnas.1806438115
pmid:30514815
pmcid:PMC6305006
fatcat:pecarj7cyvdwha35nqooiszbvm
Electrostatically constrained α-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide
2009
International Journal of Biochemistry and Cell Biology
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We found a strong correlation between the anti-HIV-1 activities of these peptides and the thermostabilities of the 6-helix bundles that are formed with these peptides. ...
We also obtained the crystal structure of SC34EK in complex with a 36 amino acid sequence (N36) comprising the amino terminal heptad repeat of HIV-1. ...
Acknowledgements This work was supported in part by grants for the Promotion of AIDS Research from the ...
doi:10.1016/j.biocel.2008.08.039
pmid:18834950
fatcat:pvfrn7zy5nbdpe2dok2jgqgpmq
Watching proteins in motion
2009
Genome Biology
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A report of the 23rd Protein Symposium 'Proteins in Motion', ...
Madhavi Kolli (University of Massachusetts Medical School, Worcester, USA) provided evidence that in patients treated with HIV protease inhibitors, mutations in the protease and its substrates coevolve ...
This reservoir of stability is thought to serve as a capacitor for functional evolution of these proteins by maintaining structure in the face of destabilizing mutations that increase the potential for ...
doi:10.1186/gb-2009-10-10-316
pmid:19863776
pmcid:PMC2784317
fatcat:2422i23gt5gjtixvninogskvby
Potts Hamiltonian models of protein co-variation, free energy landscapes, and evolutionary fitness
2017
Current Opinion in Structural Biology
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Potts Hamiltonian models of protein sequence co-variation are statistical models constructed from the pair correlations observed in a multiple sequence alignment (MSA) of a protein family. ...
These models are powerful because they capture higher order correlations induced by mutations evolving under constraints and help quantify the connections between protein sequence, structure, and function ...
Acknowledgement This work was supported by the National Institutes of Health P50 GM103368 and R01 GM30580. ...
doi:10.1016/j.sbi.2016.11.004
pmid:27870991
pmcid:PMC5869684
fatcat:iunvrurryzbuvjugfw3uof6eg4
HIV-1 anchor inhibitors and membrane fusion inhibitors target distinct but overlapping steps in virus entry
2019
Journal of Biological Chemistry
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Although we found a strong correlation between Env stability and resistance to HR2-based fusion inhibitors, such correlation was not observed for Env stability and VIR165 resistance. ...
In contrast, resistance mutations in the HR1-binding site for the fusion inhibitors did not cause cross-resistance to VIR165. ...
Overall, there was a very strong correlation between Env stability and resistance to T20 (Fig. 3D ) and a moderate correlation with resistance to T2635 (Fig. 3E) , supporting the link between Env stability ...
doi:10.1074/jbc.ra119.007360
pmid:30696772
pmcid:PMC6463712
fatcat:65si2pei2reohauln47r2koihy
Comparison of a retroviral protease in monomeric and dimeric states
2019
Acta Crystallographica Section D: Structural Biology
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Such a water molecule is completely unique not only in retropepsins but also in aspartic proteases in general. The C7A and C106A mutations do not influence the conformation of the protein. ...
Retroviral proteases (RPs) are of high interest owing to their crucial role in the maturation process of retroviral particles. ...
Funding information This work was supported by a grant (RVO 61388963) from the ASCR to IP. ...
doi:10.1107/s2059798319011355
pmid:31588922
fatcat:ygohm6cazrgrflgl5jaqdufx54
Implications for Viral Capsid Assembly from Crystal Structures of HIV-1 Gag1-278and CAN133-278†,‡
2006
Biochemistry
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) in the mature HIV-1 particle, and makes an important interaction with the cellular protein cyclophilin A (CypA). ...
Gag, the major structural protein of retroviruses such as HIV-1, comprises a series of domains connected by flexible linkers. ...
We believe that this mutant provides a good model for the wild-type protein for three reasons. (1) It occurs in the middle of an exposed and inherently flexible 18-residue loop. (2) A related mutation ...
doi:10.1021/bi060927x
pmid:16981686
fatcat:msvp3d3ugzh6feg5begvpe5elm
Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: Insights into mechanisms of general viral fusion and inhibitor design
2014
Protein Science
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In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed ...
A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. ...
Karen Siu for critical reading of the manuscript. ...
doi:10.1002/pro.2442
pmid:24519901
pmcid:PMC4005712
fatcat:ir42jkvtfzb47aqmskmzy4h6yi
Human Leukocyte Antigen (HLA) Class I Down-Regulation by Human Immunodeficiency Virus Type 1 Negative Factor (HIV-1 Nef): What Might We Learn From Natural Sequence Variants?
2012
Viruses
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HIV-1 causes a chronic infection in humans that is characterized by high plasma viremia, progressive loss of CD4+ T lymphocytes, and severe immunodeficiency resulting in opportunistic disease and AIDS. ...
We argue that efforts to fully understand the critical role of Nef for HIV-1 pathogenesis will require greater analysis of patient-derived sequences to elucidate subtle differences in immune evasion activity ...
MAB holds a Canada Research Chair, Tier 2, in Viral Pathogenesis and Immunity. ...
doi:10.3390/v4091711
pmid:23170180
pmcid:PMC3499827
fatcat:jxi7z6ffdzgmjg3fixsivzuz6q
Design of Mutation-resistant HIV Protease Inhibitors with the Substrate Envelope Hypothesis
2007
Chemical Biology and Drug Design
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There is a clinical need for HIV protease inhibitors that can evade resistance mutations. ...
The value of HIV protease (HIVP) as a drug-target is powerfully validated by the fall in morbidity and mortality of HIV-positive individuals when the protease inhibitors were introduced to clinical practice ...
Acknowledgments We thank Ellen A. Nalivaika for providing protease specimens. Some protease inhibitors were obtained through the AIDS Research and Reference Reagent Program, NIAID, NIH. ...
doi:10.1111/j.1747-0285.2007.00514.x
pmid:17539822
fatcat:gpf3sdaglbegpfvrjlqsxuu42a
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